Ovarian Cancer Peritoneal Carcinomatosis Research Articles

Three-dimensional dynamics of mesothelin-targeted CAR.CIK lymphocytes against ovarian cancer peritoneal carcinomatosis

Intraperitoneal cellular immunotherapy with CAR-redirected lymphocytes is an intriguing approach to target peritoneal carcinomatosis (PC) from ovarian cancer (OC), which is currently evaluated in clinical trials. PC displays a composite structure with floating tumor cells within ascites and solid-like masses invading the peritoneum. Therefore, a comprehensive experimental model is crucial to optimize CAR-cell therapies in such a peculiar environment. Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a “floating-like” 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a “solid-like” context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. Our findings provide currently unknown therapeutically relevant information on intraperitoneal approaches with CAR.CIK, supporting further developments and improvements for clinical studies in the context of locoregional cell therapy approaches for patients with PC from OC.

Perspectives of pressurized intraperitoneal aerosol chemotherapy in terms of primary ovarian cancer with peritoneal carcinomatosis treatment

The relevance of the problem of increasing the effectiveness of standard treatment of ovarian cancer is determined by the following characteristics of the disease: high one‑year mortality, high recurrence rate and unsatisfactory results of their treatment. Peritoneal carcinomatosis in ovarian cancer occurs in 65–70 % of cases. The standard modern approach to the treatment of ovarian cancer is a combination of surgical treatment and systemic intravenous chemotherapy. At the same time, more than 70 % of ovarian cancer cases are first diagnosed at stages III–IV. However, despite the successes in the field of surgery and drug treatment, the five‑year survival rate is no more than 24 % at the III and 4.6 % at the IV stage of the disease. One of the frontiers of ovarian cancer resistance to therapy is peritoneal carcinomatosis. Its resistance to therapy is due to the low bioavailability of cytostatics in metastases on the peritoneum to almost zero. In order to increase bioavailability, various forms of intra‑abdominal chemotherapy are used. The technique of pressurized intraperitoneal aerosol chemotherapy (PIPAC) has a number of advantages over other methods of intra‑abdominal antitumor treatment. These advantages include the uniform distribution of cytostatics over the peritoneum, the absence of penetration of cytostatics beyond the peritoneum, which allows PIPAC to be combined with systemic chemotherapy, low trauma and good tolerability of the procedure. PIPAC was implemented into clinical practice in 2011, and since then has been widely used in a number of foreign and domestic clinics. The conducted studies confirm the safety of the technique and its effectiveness against peritoneal carcinomatosis. The data of multicenter studies and the analysis of available literature data, as well as the successful own experience of PIPAC use create prerequisites for investigating the effectiveness of intra‑abdominal aerosol chemotherapy under pressure in relation to peritoneal carcinomatosis in ovarian cancer.

Dynamic assessment of intraperitoneal aerosol chemotherapy under pressure impact on peritoneal carcinomatosis in ovarian cancer (immediate results)

Purpose of the study. Dynamic assessment of the direct impact of pressurized intraperitoneal aerosol chemotherapy (PIPAC) on peritoneal carcinomatosis in ovarian cancer.Patients and methods. The study involved 164 people with visually detectable and morphologically verified ovarian cancer with peritoneal carcinomatosis of the peritoneum (IIIb-IIIc stages of ovarian cancer). All patients underwent combined treatment of ovarian cancer, which included primary cytoreduction and 6 courses of сhemotherapy according to the TC scheme. In the main group, the standard treatment was supplemented with 3 sessions of PIPAC. Statistical processing was carried out by analyzing the exact criterion of the Wilcoxon-Mann-Whitney sums, the distribution of patients in groups by age and peritoneal lesion was estimated. It was found that the distribution of the analyzed parameters was random. The distribution in the groups by stages of the disease was homogeneous, which is justified by the use of the Barnard criterion. The dynamics of the parameters of the study was evaluated by the methods of basic statistics. Used software packages: MedCals, Statistica.Results. The results obtained demonstrate a distinct positive dynamics in the group of patients receiving PIPAC in addition to standard treatment of newly diagnosed ovarian cancer: a significant decrease in the peritoneal cancer index, therapeutic pathomorphosis in peritoneal samples during treatment, reduction of ascites.Conclusion. The team of authors managed to establish that PIPAC simultaneously with standard combined treatment for newly diagnosed ovarian cancer with peritoneal carcinomatosis makes it possible to achieve a dynamic regression effect of peritoneal carcinomatosis of the peritoneum, morphological regression of carcinomatosis and complete resorption of ascites in the vast majority of treated patients. The revealed therapeutic effect was prolonged and persistent with an objective assessment 6 months after the end of treatment.

Can a morphological description of the peritoneal carcinomatosis in advanced ovarian cancer add prognostic information? Analysis of 1686 patients of the tumor bank ovarian cancer.

Peritoneal carcinomatosis in ovarian cancer is frequent and generally associated with higher stage and poorer outcome. The clinical features of peritoneal carcinomatosis are diverse and their relevance for surgical and long-term outcome remains unclear. We conducted this prospective study to describe intraoperatively the different features of peritoneal carcinomatosis(PC) and correlate them with clinicopathological features, progression-free(PFS) and overall survival (OS),. We performed a systematic analysis of all patients with documented intraoperative PC and a primary diagnosis of epithelial ovarian, tubal, or peritoneal cancer from January 2001 to September 2018. All data were evaluated by using the systematic tumor bank tool. Specific PC features included texture(soft-hard), consistency(coarse-fine or both), wet vs dry(PC with ascites vs. PC without ascites), and localization(diffuse-local). PC characteristics were then evaluated for correlation with age, FIGO-stage, histology, lymph-node involvement, grade, and presence of residual tumor at primary surgery. Moreover, the influence of PC characteristics on OS and PFS was analyzed. A total of 1686 patients with PC and primary epithelial ovarian cancer were included. Majority of the patients were characterized by diffuse PC(73.9%). The majority of peritoneal nodules were fine in texture (55.3%) and hard in consistency (87.4%). Moreover, 27.6% of patients had dry PC. Diffuse PC localization was significantly associated with higher FIGO-stage (p<0.001), high-grade (p=0.003) and serous tumors (p=0.006) as well as residual tumor as compared to local PC (p<0.001). Wet PC also significantly correlated with diffuse localization (p <0.001) and residual tumor as compared to dry PC (p<0.001). Coarse PC was significantly associated with residual tumor as compared to fine PC (p=0.044). All other PC features didn´t correlate with clinicopathological features. As for survival outcomes, diffuse peritoneal localization (p<0.001), wet PC (p<0.001), and additional lymph node involvement (p<0.001) were associated with lower OS and PFS rates. Other PC features did not significantly impact survival. Diffuse localization of peritoneal carcinomatosis was significant predictor of recurrence. Lower OS and PFS were associated with diffuse peritoneal localization, wet PC, and additional lymph node involvement. Further prospective trials are warranted with the inclusion of translational research aspects to better understand the different peritoneal carcinomatosis patterns.

Review Article on Epithelial Ovarian Cancer with Peritoneal Metastasis

Introduction: Many advances have emerged in the management of peritoneal metastases of ovarian cancer origin, widely known as the most common gynaecological malignancy. This review is an update of the current management algorithm of peritoneal carcinomatosis of ovarian cancer, including screening methods, biomarkers and surgical techniques, in an effort to shed some light into this difficult to treat malignancy. Objective: To assess awareness in the management of epithelial ovarian cancer (EOC) with peritoneal metastasis with updated therapeutic standpoints.

Ovarian cancer peritoneal carcinomatosis: a narrative review

Ovarian cancer peritoneal carcinomatosis: a narrative review

Treatment of gastric and ovarian cancer peritoneal carcinomatosis with PIPAC: initial experience of Lithuanian center

Background: Peritoneal malignancies include primary and metastatic cancer of the peritoneal cavity. The most common origin for peritoneal metastasis is ovarian, gastric, and colorectal cancers. Irrespective of the origin, peritoneal metastases represent the advanced disease and are associated with poor long-term outcomes. The minimally invasive approach of PIPAC allows repeated applications and objective assessment of tumor response by comparing histological samples. This study aimed to investigate the initial experience with PIPAC in the Baltic region.

Selectins: An Important Family of Glycan-Binding Cell Adhesion Molecules in Ovarian Cancer.

Ovarian cancer is the most lethal gynecological malignancy worldwide. Unlike most other tumor types that metastasize via the vasculature, ovarian cancer metastasizes predominantly via the transcoelomic route within the peritoneal cavity. As cancer metastasis accounts for the majority of deaths, there is an urge to better understand its determinants. In the peritoneal cavity, tumor-mesothelial adhesion is an important step for cancer dissemination. Selectins are glycan-binding molecules that facilitate early steps of this adhesion cascade by mediating heterotypic cell-cell interaction under hydrodynamic flow. Here, we review the function and regulation of selectins in peritoneal carcinomatosis of ovarian cancer, and highlight how dysregulation of selectin ligand biogenesis affects disease outcome. Further, we will introduce the latest tools in studying selectin-glycan interaction. Finally, an overview of potential therapeutic intervention points that may lead to the development of efficacious therapies for ovarian cancer is provided.

Ovarian cancer subtypes and survival in relation to three comprehensive imaging parameters

BackgroundOvarian cancer (OC) is usually detected in late clinical stages, and imaging at diagnosis is crucial. Peritoneal carcinomatosis (PC) and cardio phrenic lymph nodes (CPLN) are pathological findings of computed tomography (CT) and are relevant for surgical planning. Furthermore, mammographic breast density (BD) has shown an association with OC risk and might be prognostically relevant. However, it is not known if PC, CPLN, and BD are associated with aggressive OC subtypes and impaired OC survival. Herein, we investigated associations between three comprehensive image parameters and OC subtypes and survival.MethodsThe Malmö Diet and Cancer Study is a prospective study that included 17,035 women (1991–1996). Tumor information on 159 OC and information on OC specific survival (last follow-up, 2017-12-31) was registered. The CT and mammography closest to diagnosis were evaluated (Peritoneal Carcinomatosis Index PCI, CPLN, and BD). Associations between CT-PCI, CPLN, and BD vs. clinical stage [stage I vs. advanced stage (II-IV), histological type/grade (high grade serous and endometrioid vs. other subtypes], and OC-specific survival were analyzed by logistic and Cox regression.ResultsThere was a significant association between higher CT-PCI score and advanced clinical stage (adjusted OR 1.26 (1.07–1.49)), adjusted for age at diagnosis and histological type/grade. Increasing CT-PCI was significantly associated with impaired OC specific survival (adjusted HR 1.04 (1.01–1.07)), adjusted for age at diagnosis, histological type/grade, and clinical stage. There was no significant association between PCI and histological type/grade, nor between BD or CPLN vs. the studied outcomes.ConclusionsImage PCI score was significantly associated with advanced clinical stages and impaired OC survival. An objective approach (based on imaging) to scoring peritoneal carcinomatosis in ovarian cancer could help surgeons and oncologists to optimize surgical planning, treatment, and care.

Securing the Payload, Finding the Cell, and Avoiding the Endosome: Peptide-Targeted, Fusogenic Porous Silicon Nanoparticles for Delivery of siRNA.

Despite the promise of ribonucleic acid interference therapeutics, the delivery of oligonucleotides selectively to diseased tissues in the body, and specifically to the cellular location in the tissues needed to provide optimal therapeutic outcome, remains a significant challenge. Here, key material properties and biological mechanisms for delivery of short interfering RNAs (siRNAs) to effectively silence target-specific cells in vivo are identified. Using porous silicon nanoparticles as the siRNA host, tumor-targeting peptides for selective tissue homing, and fusogenic lipid coatings to induce fusion with the plasma membrane, it is shown that the uptake mechanism can be engineered to be independent of common receptor-mediated endocytosis pathways. Two examples of the potential broad clinical applicability of this concept in a mouse xenograft model of ovarian cancer peritoneal carcinomatosis are provided: silencing the Rev3l subunit of polymerase Pol ζ to impair DNA repair in combination with cisplatin; and reprogramming tumor-associated macrophages into a proinflammatory state.

Pain Mechanisms in Peritoneal Diseases Might Be Partially Regulated by Estrogen.

To identify factors influencing the differential pain pathogenesis in peritoneal endometriosis (pEM) and peritoneal carcinomatosis in ovarian cancer (pOC), we undertook an experimental study. Tissue samples of 18 patients with pEM, 15 patients with pOC, and 15 unaffected peritoneums as controls were collected during laparoscopy or laparotomy. Immunohistochemical stainings were conducted to identify nerve fibers and neurotrophins in the tissue samples. Additionally, 23 pEM fluids, 25 pOC ascites fluids, and 20 peritoneal fluids of patients with myoma uteri as controls were collected. In these fluids, the expression of neurotrophins was evaluated. The effects of peritoneal fluids and ascites on the neurite outgrowth of chicken sensory ganglia were estimated by using a neuronal growth assay. An electrochemiluminescence immunoassay was carried out to determine the expression of estrogen in the peritoneal fluids and ascites. The total and sensory nerve fiber density was significantly higher in pEM than in pOC ( P < .001 and P < .01). All neurotrophins tested were present in tissue and fluid samples of pEM and pOC. Furthermore, the neurotrophic properties of pEM and pOC fluids were demonstrated, leading to sensory nerve fiber outgrowth. Estrogen concentration in the peritoneal fluids of pEM was significantly higher compared to ascites of pOC ( P < .001). The total and sensory nerve fiber density in the tissue samples as well as the estrogen expression in the peritoneal fluid of pEM was considerably higher than that in pOC, representing the most notable difference found in both diseases. This might explain the differential pain perception in pEM and pOC. Therefore, estrogen might be a key factor in influencing the genesis of pain in endometriosis.

2017 Update on Ovarian Cancer Peritoneal Carcinomatosis Multimodal-Treatment Considerations.

Ovarian cancer peritoneal carcinomatosis requires a multimodal-treatment approach. Current treatment considerations are analyzed in this update and include the management of recurrent malignant ascites and the understanding of its pathophysiology, the role of peritoneal washing cytology in detecting peritoneal metastases, capsular invasion and ovarian cancer histologic type, interpretation of pretreatment Ca-125 levels at different time points of ovarian cancer therapeutic management, characteristics of 10-year survivors of high-grade ovarian cancer, and the role of lymphadenectomy in ovarian cancer peritoneal carcinomatosis. This update also includes current considerations on the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in ovarian cancer peritoneal carcinomatosis as well as relevant ongoing phase III randomized controlled trial protocols.

Peritoneal Carcinomatosis in Primary Ovarian Cancer: Ultrasound Detection and Comparison with Computed Tomography

We retrospectively compared detection rates and consistency for diagnosis of peritoneal carcinomatosis (PC) of primary ovarian cancer (OC) between ultrasound (US) and computed tomography (CT) scans in 41 patients whose PC of OC (stages IIC–IV) had been diagnosed by histopathology findings. Compared with CT detection rates, those for US were significantly higher for metastases to the pelvic area (92.3% vs. 43.6%, p < 0.001) and bowel surface (64.0% vs. 16.0%, p = 0.002); however, they did not significantly differ for other sites: omentum, diaphragm, lateral peritoneum, mesenteric, hepatic and splenic surfaces. Diagnostic consistency between US and CT scans were fair to moderate for splenic (κ = 0.806), hepatic (κ = 0.485), lateral peritoneum (κ = 0.450) and diaphragm (κ = 0.338) surfaces, but poorly consistent for other parts (κ = 0.144–0.229). In summary, US can complement CT scans, especially for detecting PC of primary OC metastases in pelvic and bowel surfaces.

Advantages of intraperitoneal chemotherapy in treatment of ovarian cancer peritoneal carcinomatosis

The purpose of research is a comparison of the combined antitumor effects of cytotoxic drugs used in the treatment of ovarian cancer, when administered intraperitoneally, with the effects of these drugs in mono-treatment. The study was conducted in 132 Wistar female rats inoculated intraperitoneally with ascitic tumor of the ovary. At 48 hours after inoculation of the ovarian tumor rats were administered once intraperitoneally with drugs at maximum tolerated doses, dioxadet 1.5 mg/kg of body weight, cisplatin 4 mg/kg, cyclophosphamide 100 mg/kg, paclitaxel 5 mg/kg, gemcitabine 50 mg/kg, or a combination of these drugs in half doses. Antitumor effects of the treatment were estimated by increase in survival time comparing median survival time of rats in different groups. Combinations dioxadet with cisplatin”, dioxadet with cyclophosphamide, and dioxadet with paclitaxel” have additive antitumor effects in comparison with the effects of these drugs administered separately. Combination dioxadet with gemcitabine did not increase the antitumor activity of the drugs.

Advantages of intraperitoneal chemotherapy in treatment of ovarian cancer peritoneal carcinomatosis

The purpose of the study is to compare antitumor activity of different drugs at their Intraperitoneal (i. p.) and intravenous (i.v.) administration in rats with ovarian cancer peritoneal carcinomatosis. The study was carried out in 124 Wistar female rats with ovarian cancer which was inoculated i. p. After ovarian cancer inoculation rats were randomized in 12 groups, 10 rats in each group. There were six groups where saline (2 ml, i.p. control group) or the drugs (dioxadet 1.5 mg/kg, cisplatin 4mg/kg, mitomycin C 1.5 mg/kg, melphalan 2 mg/kg, paclitaxel 5 mg/kg) were administered i. p. In other six groups saline (2 ml, i. v. control group) and the named above drugs at the same doses were administered i. v. Antitumor effects of the treatment were estimated by increase in survival time (IST) comparing median survival time of rats in different groups. IST for i.p. administration of dioxadet, cisplatin, melphalan, mitomycin C and paclitaxel were 79 % (p &lt; 0.001), 88 % (p &lt; 0.001), 114 % (p &lt; 0.001), 35 % (p &lt; 0.002) and 45 % (p &lt; 0.001) correspondingly compared to i.p. control group while for i.v. administration of these drugs IST were 5 % (p = 0.796), 14 % (p = 0.315), 19 % (p = 0.631), 152 % (p &lt; 0.001) and 81 % (p = 0.023) correspondingly compared to i. v. control group. Thus, i. p. chemotherapy with alkylating agents dioxadet, cisplatin and melphalan is much more effective then their i. v. administration, while antitumor effects of i. p. and i. v. administration of paclitaxel were similar and only mitomycin C is more active at i. v. administration.

Place de la chimiothérapie hyperthermique intrapéritonéale (CHIP) dans la prise en charge du cancer de l’ovaire : expérience monocentrique institutionnelle

The peritoneal carcinomatosis of ovarian cancer led to the development of optimal cytoreduction surgery completed by hyperthermic intraperitoneal chemotherapy (HIPEC). The main goal of this study is to evaluate the feasibility, tolerance and efficacy of this technique in patients with ovarian cancer. A retrospective monocentric study has evaluated 43patients with HIPEC procedures from 1995 to 2009. After a complete cytoreduction surgery, a HIPEC procedure with cisplatin is performed. Data on complications and survival parameters were collected. Prognostic factors were also analyzed. Post-surgery complications included one death due to a septic shock (2.3%) and six patients have presented major complications (13.9%). The median of overall survival and progression free survival were 53.6 and 39months, respectively. Patients with a primary complete surgical cytoreduction of the peritoneal carcinomatosis presented overall survival length of 131months versus 84months without initial complete resection (P<0.0001). Surgical cytoreduction combined with HIPEC is a feasible procedure with acceptable morbid-mortality rates. The initial complete resection of the peritoneal carcinomatosis significantly increases survival and represents a strong prognostic factor.

Neoadjuvant intraperitoneal chemotherapy with paclitaxel for the radical surgical treatment of peritoneal carcinomatosis in ovarian cancer: a prospective pilot study

The admitted benefits of intraperitoneal chemotherapy during postoperative administration for the treatment of peritoneal carcinomatosis from ovarian origin are limited by their associated morbidity and restricted diffusion by the presence of multiple intra-abdominal adherences. The purpose of the study was to evaluate the security, effectiveness, and cytoreduction optimization of intraperitoneal paclitaxel administration previously to radical surgery/peritonectomy/HIPEC (hyperthermic intraoperative intraperitoneal chemotherapy) either in monotherapy or combined with intravenous carboplatin. Prospective pilot study of 10 patients with ovarian peritoneal carcinomatosis in stage IIIc-FIGO without previous treatment. After staging of the diseases by laparoscopy, five patients received paclitaxel by weekly intraperitoneal administration (60mg/m(2), 10 cycles), and other five patients additionally received intravenous carboplatin every 21days (AUC 6, 4 cycles). Subsequently radical surgery/peritonectomy with HIPEC was performed. The presence of moderate abdominal pain was the most common (70%) side effect associated with neoadjuvant paclitaxel intraperitoneal administration. The intravenous carboplatin administration was not associated with significant increase in adverse effects. It boosted intraperitoneal paclitaxel-associated antitumoral activity with a high average decrease in Index Cancer Peritoneal (21.2 vs. 14.4, P=0.066) and CA 125(1,053 vs. 346, P=0.043). All the patients who received combined neoadjuvant chemotherapy obtained R0 cytoreduction. Five-year overall survival was 62%. The intraperitoneal paclitaxel weekly administration combined with intravenous carboplatin administration prior to radical surgery/peritonectomy with HIPEC is a safe and effective option in the treatment of ovarian peritoneal carcinomatosis. This study shows the possibility to investigate other forms of intraperitoneal chemotherapy and their combinations thoroughly.

Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery in ovarian cancer peritoneal carcinomatosis: systematic review of current results

Advanced and recurrent ovarian cancer results in extensive spread of tumor on the peritoneal surfaces of the abdomen and pelvis. We collectively review studies in the literature that report the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer peritoneal carcinomatosis. An electronic search of all relevant studies published in peer-reviewed journals before May 2009 was performed on three databases. The quality of each study was independently assessed and classified according to the time point of HIPEC use in various setting of ovarian cancer from the consensus statement of the Peritoneal Surface Oncology Group. Clinical efficacy was synthesized through a narrative review with full tabulation of the results of each included study. Nineteen studies each of more than ten patients reporting treatment results of HIPEC of patients with both advanced and recurrent ovarian cancer were included and data were extracted. All studies were observational case series. The overall rate of severe perioperative morbidity ranged from 0 to 40% and mortality rate varied from 0 to 10%. The overall median survival following treatment with HIPEC ranged from 22 to 64 months with a median disease-free survival ranging from 10 to 57 months. In patients with optimal cytoreduction, a 5-year survival rate ranging from 12 to 66% could be achieved. Despite the heterogeneity of the studies reviewed, current evidence suggest that complete CRS and HIPEC may be a feasible option with potential benefits that are comparable with the current standard of care. A randomized trial is required to establish the role of HIPEC in ovarian cancer.

Intra-operative intra-peritoneal chemotherapy with cisplatin in patients with peritoneal carcinomatosis of ovarian cancer

BackgroundIntra-peritoneal (i.p.) chemotherapy is an encouraging treatment option for ovarian cancer with peritoneum involvement in addition with intravenous (i.v.) chemotherapy. Intra-operative i.p. chemotherapy is an interesting method of administration by enhancing the diffusion of chemotherapy. This study had assessed the feasibility of intra-operative i.p. chemotherapy in patients with peritoneal carcinoma of ovarian cancer.MethodsFrom January 2003 to February 2006, 47 patients with stage III ovarian cancer were treated with standard paclitaxel carboplatin intravenous chemotherapy and debulking surgery with intra-operative i.p. chemotherapy. After optimal cytoreductive surgery, defined by no unresectable residual disease > 1 cm, i.p. chemotherapy was performed during surgery. The peritoneal cavity was filled by 3 litres of isotonic saline pre-heated at 37 degrees and 90 mg of cisplatin. The sequence was repeated twice during 2 hours based on previous published studies which optimized the cisplatin dosage and exposure duration. Optimal diffusion was obtained by stirring by hands during the 2 hours.ResultsMedian age was 59.6 years. No severe haematological or non-haematological toxicity induced by intra operative i.p. chemotherapy was reported. No patient died due to the complications of surgery or the i.p. chemotherapy. No neurotoxicity occurred, and one patients had renal impairment.ConclusionThis study demonstrates the feasibility of intra-operative i.p. chemotherapy with cisplatin after optimal resection of peritoneal tumor nodules. Further randomized trials are planned to investigate the clinical benefit of this therapeutic modality.

Intraoperative intraperitoneal (IP) chemotherapy with cisplatin and escalated dose of epinephrine in patient with recurrent peritoneal carcinomatosis of ovarian cancer: A phase I study

16019 Background: IP epinephrine (E) has been shown to enhance the accumulation and antitumor activity of IP cisplatin in rats with peritoneal carcinomatosis (Duvillard et al. Int J Cancer, 1999). E induces a vasoconstriction of peritoneal vascular bed which limits platin peritoneal leakage and enhances drug penetration into tumor nodules. Results of a phase I study with the association of IP E and IP cisplatin in patient with refractory peritoneal carcinomatosis has been reported (Molucon-Chabrot et al, Anticancer Drugs, 2006). We conducted a phase I study to evaluate intraoperative IP chemotherapy with the association of cisplatin and escalated dose of E. Methods: 18 patients (pts) with recurrent ovarian cancer were enrolled. The median age was 56 years old (range 42–66). After an optimal cytoreductive surgery, IP chemotherapy was performed during surgery by filling twice the peritoneal cavity with 3 liters of an isotonic saline pre heated at 37°C and 90 mg of cisplatin associated with increasing concentrations of E during 1 hour. Results: E was escalated according to the following dosage: 0, 1, 2, 3 mg/L (3 pts by step). No toxicity was observed during and after intraoperative IP chemotherapy in the first 10 patients. The 2nd patient included in the 3 mg/L level of E experienced a tachycardia ≥ 120/min, ventricular extrasystoles (VES) ≥ 2/min, increase of troponine plasmatic concentration without significant electric sign of cardiac ischemia. The 3rd patient at this level experienced a tachycardia ≥ 120/min with ventricular VES ≥ 2/min and no increase of troponine concentration or electric sign of cardiac ischemia. According to the protocol design, 6 additional patients were included in the lower dose of 2 mg/L of E and no toxicity occurred. One can consider that the recommended dose of E was established. Conclusion: The combination of IP E with IP cisplatin in intraoperative chemotherapy after optimal cytoreductive surgery is feasible. The limiting toxicity was the cardiovascular effect which occurred with 3 mg/L dose of E. A phase II-III study is planned to investigate if IP chemotherapy adds to a second look surgery for the initial treatment of stage III ovarian carcinoma. No significant financial relationships to disclose.